The Logical Next Step
When I began my PhD research almost 40 years ago, nuclear medicine research was almost entirely focused on diagnosis. And so my work aimed at looking for radionuclides suited to diagnostic applications, either by single photon imaging or PET. As my work progressed, Richard Spencer approached the group about an idea that he had regarding therapy. He was looking for short-lived radionuclides that could be injected directly into the vasculature of the tumor to achieve a therapeutic result.
At that point, it was becoming clear that high-linear energy transfer (LET) emitters had a role to play in therapy, though it was embryonic at that point. We looked at several systems and thought a couple of generator systems had some good potential. One was to utilize Bi-211, which had a half-life of about two minutes. So we spent the next couple of years designing and testing generator ideas to harness that capability.
In parallel with my efforts, the monoclonal antibody was developed by Kohler and Milstein. What a remarkable tool that could be! One could develop a single antibody against almost anything imaginable and then have a super-selective agent to identify it. Almost immediately, the power of that biomolecule was investigated for its potential as a radiolabeled agent. And, given its size, the potential for a variety of labeling techniques also was recognized. And labeling was not limited to diagnostic radionuclides. Therapeutic radionuclides also could be utilized as labels and I-131 was simultaneously used as both a diagnostic and therapeutic. The problem was that I-131 is a terrific isotope if a substantial percentage of the injected dose can localize, as is the case with thyroid cancer. But the limitations of the monoclonals were soon apparent as injected doses in humans were a fraction of a percent. And to make matters worse, the antibodies that made it into early clinical application also were raised against some of the most radioresistant tumors such as melanoma. So the initial excitement dimmed considerably when the potential for radioimmunotherapy stalled.
The good news is that the practitioners in the field were now alerted to the potential to develop a targeting molecule that could identify virtually anything of interest. And as radiolabeling technology matured, we also identified chemistry that would maintain the bioactivity of the molecule while preserving the bond between the radionuclide and the targeting molecule.
This presents a classic case of translational medicine wherein we use diagnostic radionuclides to demonstrate the efficacy of the targeting system in vitro and in preclinical imaging, use the same tracer to predict the radiation dose that would be delivered from any one of the radionuclides of interest, and finally to select the right radioconjugate for the job.
As we have matured even farther with our ability to utilize peptides or other internalizing ligands for targeting instead of antibodies, we also can make even better use of high LET emitters such as alpha particle or Auger electron emitters for therapy. To me, this is one of the most powerful areas to explore in the field of nuclear medicine. And we should not limit ourselves to cancer as the only area of pursuit. There are devastating diseases that could be approached using therapeutic nuclear medicine to treat effectively such as synovitis in arthritis, infectious agents that are resistant to conventional therapy, and in vitro application in autologous marrow transplant. Let us use the power of molecular imaging to introduce the potential of nuclear molecular medicine.